Lysyl oxidase (LOX) in vascular remodelling

Mar Orriols; Anna Guadall; María Galán; Ingrid Martí-Pàmies; Saray Varona; Ricardo Rodríguez-Calvo; Ana María Briones; María A. Navarro; Alicia de Diego; Jesús Osada; José Martínez-González; Cristina Rodríguez

doi:10.1160/TH14-01-0024

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2014; 112(04): 812-824
DOI: 10.1160/TH14-01-0024

Animal Models

Schattauer GmbH

Lysyl oxidase (LOX) in vascular remodelling

Insight from a new animal model

Mar Orriols^¶

¹Centro de Investigación Cardiovascular, CSIC-ICCC. Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain

,

Anna Guadall^¶

¹Centro de Investigación Cardiovascular, CSIC-ICCC. Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain

,

María Galán

¹Centro de Investigación Cardiovascular, CSIC-ICCC. Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain

,

Ingrid Martí-Pàmies

¹Centro de Investigación Cardiovascular, CSIC-ICCC. Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain

,

Saray Varona

¹Centro de Investigación Cardiovascular, CSIC-ICCC. Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain

,

Ricardo Rodríguez-Calvo

¹Centro de Investigación Cardiovascular, CSIC-ICCC. Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain

,

Ana María Briones

²Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid, Spain

,

María A. Navarro

³Facultad de Veterinaria, Universidad de Zaragoza, CIBEROBN, Zaragoza, Spain

,

Alicia de Diego

⁴Unidad de Transgénesis, Instituto Aragonés de Ciencias de la Salud, Zaragoza, Spain

,

Jesús Osada

³Facultad de Veterinaria, Universidad de Zaragoza, CIBEROBN, Zaragoza, Spain

,

José Martínez-González^‡

¹Centro de Investigación Cardiovascular, CSIC-ICCC. Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain

,

Cristina Rodríguez^‡

¹Centro de Investigación Cardiovascular, CSIC-ICCC. Instituto de Investigación Biomédica Sant Pau (IIB Sant Pau), Barcelona, Spain

› Institutsangaben

Abstract

Summary

Lysyl oxidase (LOX) is an extracellular matrix-modifying enzyme that seems to play a critical role in vascular remodelling. However, the lack of viable LOX-deficient animal models has been an obstacle to deep in LOX biology. In this study we have developed a transgenic mouse model that over-expresses LOX in vascular smooth muscle cells (VSMC) to clarify whether LOX could regulate VSMC phenotype and vascular remodelling. The SM22 proximal promoter drove the expression of a transgene containing the human LOX cDNA. Two stable transgenic lines, phenotypically indistinguishable, were generated by conventional methods (TgLOX). Transgene expression followed the expected SMC-specific pattern. In TgLOX mice, real-time PCR and immunohistochemistry evidenced a strong expression of LOX in the media from aorta and carotid arteries, coincident with a higher proportion of mature collagen. VSMC isolated from TgLOX mice expressed high levels of LOX pro-enzyme, which was properly secreted and processed into mature and bioactive LOX. Interestingly, cell proliferation was significantly reduced in cells from TgLOX mice. Transgenic VSMC also exhibited low levels of Myh10 (marker of SMC phenotypic switching), PCNA (marker of cell proliferation) and MCP-1, and a weak activation of Akt and ERK1/2 in response to mitogenic stimuli. Accordingly, neointimal thickening induced by carotid artery ligation was attenuated in TgLOX mice that also displayed a reduction in PCNA and MCP-1 immunostaining. Our results give evidence that LOX plays a critical role in vascular remodelling. We have developed a new animal model to study the role of LOX in vascular biology.

Keywords

Vascular remodelling - smooth muscle cells - cell proliferation - extracellular matrix

Volltext

Referenzen

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